The overarching aim of this Program's renewal is to clarify the mechanisms of methamphetamine (METH) potentiation of HIV neural injury. In addition, given the notable prevalence of coinfection with hepatitis C, as well as the growing awareness of HCV as a potential co-factor in neural injury, studies are proposed to examine the separate and combined effects of METH, HIV, and HCV. Scientific hypotheses for the Program are based on an overall model proposing that METH, HIV, and HCV can act both directly and indirectly through immune cell activation to produce oxidative stress leading to injury in specific neural circuitries. The Program has assembled a multidisciplinary team to approach the hypotheses in a multifaceted and translational manner through six human Projects (Neurocognitive, Neuromotor, fMRI, Carbon 13 Spectroscopy, Biomarkers, Neurobiology) and one Animal Models Project, designed to reflect, as closely as possible, the research in the human Projects. Innovative directions proposed include deployment of neurocognitive, neuromotor, and neuroimaging methods hypothesized to be more sensitive and specific to detection of underlying mechanisms of injury by the three risk factors, as indicated by findings from the current funding period. Programmatic scientific leadership, synergy, coordination, basic evaluating, and effective use of shared resources are provided by a Core served by the Executive, Participant Accrual/Retention, Data Management and Information Systems, Statistics, and Clinical Assessment Units. Through coordinated multidisciplinary research addressing the neurotoxic effects of METH, HIV, and HCV at different levels of analysis we hope to achieve a more precise understanding of the nature and mechanisms of neural injury attributable to these factors in context. Understanding these mechanisms will provide a basis for the future development of targeted treatment interventions. [unreadable] [unreadable]